TY - JOUR
T1 - Blood-brain barrier transcytosis genes, risk of dementia and stroke
T2 - a prospective cohort study of 74,754 individuals
AU - Juul Rasmussen, Ida
AU - Tybjærg-Hansen, Anne
AU - Rasmussen, Katrine Laura
AU - Nordestgaard, Børge G
AU - Frikke-Schmidt, Ruth
PY - 2019/6/15
Y1 - 2019/6/15
N2 - To test whether genetic variants in PICALM, BIN1, CD2AP, and RIN3-suggested to be involved in blood-brain barrier amyloid-β transcytosis pathways-associate with Alzheimer's disease, all dementia, suggested vascular dementia, and stroke, and whether such associations are independent of the strong ε4 APOE risk allele. In a prospective cohort study of 74,754 individuals from the general population we genotyped PICALM (rs10792832), BIN1 (rs6733839), CD2AP (rs10948363), and RIN3 (rs10498633), and generated a weighted and a simple allele score. Multifactorially adjusted hazard ratios for the fourth quartile versus the first quartile of the weighted allele score were 1.42 (95% confidence interval 1.22-1.64) for Alzheimer's disease, and 1.33 (1.19-1.48) for all dementia. For suggested vascular dementia and stroke the corresponding estimates were 1.71 (1.18-2.49) and 1.12 (1.04-1.22), respectively. Hazard ratios were similar after APOE adjustment. Genetic variants in PICALM, BIN1, CD2AP, and RIN3 are associated with increased risk of Alzheimer's disease, all dementia, and suggested vascular dementia independent of the strong APOE ε4 allele. These findings may suggest that clathrin-mediated endocytosis in clearance of amyloid-β across the blood-brain barrier is important for the integrity of both brain tissue and cerebral vessels.
AB - To test whether genetic variants in PICALM, BIN1, CD2AP, and RIN3-suggested to be involved in blood-brain barrier amyloid-β transcytosis pathways-associate with Alzheimer's disease, all dementia, suggested vascular dementia, and stroke, and whether such associations are independent of the strong ε4 APOE risk allele. In a prospective cohort study of 74,754 individuals from the general population we genotyped PICALM (rs10792832), BIN1 (rs6733839), CD2AP (rs10948363), and RIN3 (rs10498633), and generated a weighted and a simple allele score. Multifactorially adjusted hazard ratios for the fourth quartile versus the first quartile of the weighted allele score were 1.42 (95% confidence interval 1.22-1.64) for Alzheimer's disease, and 1.33 (1.19-1.48) for all dementia. For suggested vascular dementia and stroke the corresponding estimates were 1.71 (1.18-2.49) and 1.12 (1.04-1.22), respectively. Hazard ratios were similar after APOE adjustment. Genetic variants in PICALM, BIN1, CD2AP, and RIN3 are associated with increased risk of Alzheimer's disease, all dementia, and suggested vascular dementia independent of the strong APOE ε4 allele. These findings may suggest that clathrin-mediated endocytosis in clearance of amyloid-β across the blood-brain barrier is important for the integrity of both brain tissue and cerebral vessels.
KW - Alzheimer’s disease
KW - Amyloid-β
KW - Blood–brain barrier clearance
KW - Epidemiology
KW - Stroke
KW - Vascular dementia
UR - http://www.scopus.com/inward/record.url?scp=85062721575&partnerID=8YFLogxK
U2 - 10.1007/s10654-019-00498-2
DO - 10.1007/s10654-019-00498-2
M3 - Journal article
C2 - 30830563
SN - 0393-2990
VL - 34
SP - 579
EP - 590
JO - European Journal of Epidemiology
JF - European Journal of Epidemiology
IS - 6
ER -